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PubMed1987

Halothane hepatotoxicity in Fischer 344 rats pretreated with isoniazid.

Male Fischer 344 rats were used to investigate the hepatic effects of exposure to halothane under normoxic conditions (FIO2 = 0.21) in isoniazid-treated rats. Animals were treated with saline or isoniazid (50 mg/kg) for 7 days and then were exposed to either 1% halothane or air for 2 hr. One-half of the rats from each treatment and exposure group were killed 24 hr postexposure; the remaining were killed 4 days postexposure. Twenty-four hours following halothane exposure, serum transaminase levels were significantly elevated in isoniazid- compared with saline-treated rats (i.e., aspartate aminotransferase = twofold; alanine aminotransferase = seven-fold). Cholesterol levels were significantly depressed by halothane exposure in both saline- and isoniazid-treated rats. Other serum parameters indicative of hepatic and renal function were not different: alkaline phosphatase, total protein, total bilirubin, hematocrit, uric acid, creatinine, urea nitrogen, Na+, K+, Ca2+, and inorganic phosphate. Neither saline-treated nor isoniazid-treated rats exposed to air exhibited histologic evidence of hepatic damage. Halothane-exposed rats, however, showed a circumscribed disruption of cellular morphology. The most severe lesions were observed with isoniazid-treated animals with extensive pericentral hepatocellular necrosis and infiltration by leucocytes and Kupffer cells. Serum concentrations of two products of the oxidative metabolism of halothane, trifluoroacetic acid and bromide, were significantly elevated in isoniazid- compared with saline-treated rats. Serum levels of fluoride, a product of reductive metabolism, were not different. These results strongly suggest that hepatic injury following halothane administration can be produced by intermediates of oxidative metabolism.

Alanine Transaminase↗
PubMed1976

An assessment of the carcinogenicity of isoniazid in patients with pulmonary tuberculosis.

In an assessment of the carcinogenicity of isoniazid, 3,842 adult tuberculous patients admitted to 2 sanatoria in the period 1950 to 1957 (that is, in the years immediately before and after the introduction of isoniazid) have been followed up for a mean period of over 19 years. Their mortality has been compared with that expected during the same calendar period in a general population group in England and Wales with the same age and sex distribution. The relative risk of death (the observed divided by the expected number of deaths) from all malignant neoplasms in patients first starting chemotherapy in 1950 to 1952, before the general introduction of isoniazid, was 0.8 for those who received isoniazid at some time, compared with 0.5 for those who never received it; for those first starting chemotherapy in 1953 to 1957, after the general introduction of the drug, the respective risks were 1.4 and 1.8. The relative risk of death from malignant neoplasms was 2.1 in the first 4 years after starting the treatment with isoniazid; this high relative risk is unlikely to be attributable to isoniazid and largely disappears subsequently, for in successive 4-year periods it was 1.3, 0.9, 1.2 and 1.4. The relative risks of death from all malignant neoplasms for patients receiving a total dosage of less than 50, 50-99, 100-199 and 200 g or more were 1.5, 1.5, 1.0 and 1.3, respectively. For patients receiving a maximum daily dose of less than 250 g the relative risk was 1.3, and for those receiving 250 g or more it was 1.2. There was a curious and unexplained difference in the mortality from malignant neoplasms in patients first starting chemotherapy in 1950 to 1952 (relative risk 0.6) and those first starting in 1953 to 1957 (relative risk 1.5). This is being studied further. This study has provided no evidence of a carcinogenic effect of isoniazid in a period of follow-up averaging nearly 20 years. The follow-up is being continued.

Adolescent↗
PubMed1978

The hepatic toxicity of antituberculosis regimens containing isoniazid, rifampicin and pyrazinamide.

This paper reviews hepatic toxicity during chemoprophylactic treatment with isoniazid alone, and during the treatment or retreatment of active pulmonary tuberculosis with regimens containing one or more of the drugs isoniazid, rifampicin and pyrazinamide. Chemoprophylaxis with isoniazid carries a risk of drug-induced hepatitis, and this risk needs to be weighed against the advantages of preventing tuberculosis morbidity. The risks of hepatitis during standard treatment based on isoniazid are very small, and most patients who develop hepatitis recover. Moreover, it is often doubtful whether hepatitis is in fact drug-induced, and a proportion of patients who develop it already have liver disease at the time treatment is started. The risks are acceptable in the treatment of bacteriologically active disease. There is no consistent evidence that giving rifampicin with isoniazid in the initial treatment of tuberculosis increases the risk of hepatitis; in particular, transient abnormalities in the results of tests of liver function during the early weeks of treatment do not imply serious toxicity; patients who are rapid acetylators of isoniazid are not, as has been suggested, exposed to any special risk, and patients with known liver disease can also be treated without undue risk. Retreatment regimens based on rifampicin plus ethambutol carry a low risk of hepatitis, even though patients who need retreating have often experience toxicity during their initial treatment. Frist-line or second-line regimens containing pyrazinamide in currently accepted dosages, given daily or intermittently, carry a low and acceptable risk of hepatic toxicity. Finally, current studies of daily and intermittent short-course regimens based on isoniazid, rifampicin and pyrazinamide will extend our knowledge of hepatic toxicity. Because such regimens involve small total quantitites of drugs given over short periods they are likely to give rise to less hepatic toxicity than regimens of standard duration.

Acetylation↗
PubMed1988

Controlled clinical trial of a regimen of two durations for the treatment of isoniazid resistant pulmonary tuberculosis.

Patients with pulmonary tuberculosis who were failures of primary chemotherapy with strains resistant to isoniazid or to isoniazid and streptomycin were allocated at random to receive a regimen of rifampicin and ethambutol for 6 (4RE) or 9 months (7RE), supplemented in both treatment series by streptomycin plus pyrazinamide for the first 2 months. The patients were treated in hospital for the first 2 months and thereafter treatment was supervised on a daily basis in the nearest health institution by an appointed member of staff or at home by responsible members of the community. A total of 306 patients was admitted and 226 patients remained for analysis at the end of chemotherapy, 179 with a strain resistant to isoniazid alone and 47 with a strain resistant to isoniazid and streptomycin. There were only two failures at the end of chemotherapy, one in the 6-month series who had resistance to both isoniazid and streptomycin pretreatment, and one in the 9-month series who had resistance to isoniazid alone. For the 144 patients with initial resistance to isoniazid alone assessed up to 30 months, the relapse rates were low in both series: 4% for the 72 patients in the 6-month series and 3% for the 72 patients in the 9-month series. However, for the 34 patients with resistance to both drugs, three of the 14 in the 6-month but none of 20 in the 9-month series relapsed.

Adolescent↗
PubMed1992

Colorimetric and titrimetric assay of isoniazid.

Two methods are proposed for the determination of isoniazid in pure form or in tablets. In the first method chlorpromazine hydrochloride, when treated with 2-iodoxybenzoic acid as an oxidant in 50% w/v o-phosphoric acid solution, is oxidized to chlorpromazine free radical which absorbs at 530 nm. The red free radical is readily reduced quantitatively by isoniazid to the colourless chloropromazine. The addition of isoniazid to a red solution of chlorpromazine free radical results in a decrease in absorbance in direct proportion to the quantity of isoniazid. This forms the basis for the quantitative determination of micro-quantities of isoniazid (3-18 micrograms ml-1). The second method involves the titrimetric determination of isoniazid using N-bromophthalimide as a titrant. The end-point is determined either directly using methyl red or amaranth as indicator, or by a back titration method in which a known excess of N-bromophthalimide solution is added to isoniazid solution and then the residual unreacted reagent is determined iodometrically. The results by the proposed procedures were in good agreement with those obtained by the official methods.

Chlorpromazine↗
PubMed1994

Maintenance of therapeutically active levels of isoniazid for prolonged periods in rabbits after a single implant of biodegradable polymer.

SETTING: Poor patient compliance is the serious limiting factor in the chemotherapy of tuberculosis. OBJECTIVE: To solve this problem we have been developing depot-drug delivery of antimycobacterial drugs. Earlier studies with mice using isoniazid in polylactic-co-glycolic acid (PLGA) co-polymer have shown that a single implant of the polymer could ensure sustained levels of free isoniazid for up to 8 weeks. Similar studies were not undertaken in rabbits. DESIGN: The biodegradable PLGA polymer rods containing isoniazid were implanted on the back of the rabbits under anaesthesia in an isoniazid dose of 90 mg/kg. Concentrations of isoniazid and acetylisoniazid in serum and urine were determined by the high-performance liquid chromatography (HPLC) method at close intervals up to 96 h to study the burst-size, and later at weekly intervals up to 9 weeks to study the sustained levels. RESULTS AND CONCLUSIONS: There was no abnormal release of isoniazid in the earlier periods. Concentrations of isoniazid > or = 0.2 microgram/ml were found both in serum and urine up to 63 days after implant. Urine specimen obtained at 6 weeks after giving the implant inhibited the growth of Mycobacterium tuberculosis in vitro as measured by the radiometric (Bactec) method. These findings in non-rodent animal species confirm the usefulness of the depot-drug delivery method of drug administration and warrant hopes for the successful treatment of tuberculosis avoiding the problem of non-compliance.

Animals↗
PubMed1998

Randomised trial of isoniazid versus rifampicin and pyrazinamide for prevention of tuberculosis in HIV-1 infection.

BACKGROUND: Tuberculosis is a common complication of HIV-1 infection, especially in developing countries. Practical and effective chemoprophylaxis regimens for HIV-1-related tuberculosis are needed. Our aim was to test the efficacy of isoniazid versus rifampicin with pyrazinamide for prevention of tuberculosis in HIV-1-positive individuals. METHODS: We compared the efficacy of 6 months of isoniazid with 2 months of rifampicin and pyrazinamide for prevention of tuberculosis in HIV-1-seropositive individuals. Eligible participants were aged 16-77 years, HIV-1 seropositive, had a positive purified-protein derivative (PPD) skin test reaction of at least 5 mm, and had a normal chest radiograph. Participants were randomly assigned partially supervised twice weekly isoniazid for 24 weeks or twice weekly rifampicin and pyrazinamide for 8 weeks. Participants were followed up for up to 4 years for the development of tuberculosis and survival. FINDINGS: Tuberculosis developed in 14 (3.8%) of 370 participants assigned isoniazid and 19 (5.0%) of 380 participants assigned rifampicin and pyrazinamide (Cox model rate ratio 1.3 [95% CI 0.7-2.7]). The Kaplan-Meier estimate of the risk of tuberculosis during the first 10 months after entry was 3.7% among participants who received rifampicin and pyrazinamide compared with 1.0% (p=0.03) among participants who received isoniazid, and 5.4% versus 5.1%, respectively (p=0.9) at 36 months after entry. Higher rates of tuberculosis were observed in people with baseline CD4 percentages (of total lymphocytes) of less than 20 (rate ratio 4.0 [95% CI 1.8-9.0]). There were no significant differences in total mortality at any time. INTERPRETATION: Twice-weekly isoniazid preventive therapy for 6 months or rifampicin and pyrazinamide for 2 months provided similar overall protection against tuberculosis in HIV-1-infected, PPD-positive adults. The better protection among recipients of isoniazid during the first 10 months was most likely secondary to the longer duration of chemoprophylaxis. Preventive therapy for HIV-1-seropositive, PPD-positive individuals could be practical in developing countries with a once weekly clinic visit, but optimum duration of chemoprophylaxis has not been determined.

AIDS-Related Opportunistic Infections↗
PubMed2006

Mycobacterium tuberculosis dihydrofolate reductase is a target for isoniazid.

Isoniazid is a key drug used in the treatment of tuberculosis. Isoniazid is a pro-drug, which, after activation by the katG-encoded catalase peroxidase, reacts nonenzymatically with NAD(+) and NADP(+) to generate several isonicotinoyl adducts of these pyridine nucleotides. One of these, the acyclic 4S isomer of isoniazid-NAD, targets the inhA-encoded enoyl-ACP reductase, an enzyme essential for mycolic acid biosynthesis in Mycobacterium tuberculosis. Here we show that the acyclic 4R isomer of isoniazid-NADP inhibits the M. tuberculosis dihydrofolate reductase (DHFR), an enzyme essential for nucleic acid synthesis. This biologically relevant form of the isoniazid adduct is a subnanomolar bisubstrate inhibitor of M. tuberculosis DHFR. Expression of M. tuberculosis DHFR in Mycobacterium smegmatis mc(2)155 protects cells against growth inhibition by isoniazid by sequestering the drug. Thus, M. tuberculosis DHFR is the first new target for isoniazid identified in the last decade.

Cell Proliferation↗
PubMed2001

Intravesical instillation of epirubicin, bacillus Calmette-Guerin and bacillus Calmette-Guerin plus isoniazid for intermediate and high risk Ta, T1 papillary carcinoma of the bladder: a European Organization for Research and Treatment of Cancer genito-urinary group randomized phase III trial.

PURPOSE: After transurethral resection, we compared the efficacy and side effects of weekly intravesical instillations of epirubicin, bacillus Calmette-Guerin (BCG), and BCG plus isoniazid during a 6-week interval followed by 3 weekly maintenance instillations at months 3, 6, 12, 18, 24, 30 and 36 in patients with intermediate and high risk Ta, T1 bladder cancer. MATERIALS AND METHODS: A total of 957 patients were randomized at 44 institutions in a phase III multicenter trial. RESULTS: The time to first recurrence was significantly longer in patients treated with BCG and BCG plus isoniazid compared to epirubicin (p = 0.0001) but there was no difference between the 2 BCG regimens (p = 0.27). Progression to muscle invasive cancer was rare (5%) and did not differ significantly among the 3 arms (p = 0.12). Drug induced cystitis was observed in 31% of the patients treated with epirubicin, 42% BCG and 45% BCG plus isoniazid. Systemic side effects, such as fever and malaise, were not observed in patients treated with epirubicin, but were noted in 31% BCG and 36% BCG plus isoniazid. CONCLUSIONS: Intravesical BCG with or without isoniazid provokes more side effects than epirubicin. Prophylactic isoniazid does not reduce the side effects of BCG, while BCG with or without isoniazid prolongs the time to first recurrence compared to epirubicin. Further followup is required before long-term conclusions can be made for progression-to-muscle invasive disease and survival.

Administration, Intravesical↗
PubMed1990

Inhibition of leukotriene omega-oxidation by isonicotinic acid hydrazide (isoniazid).

Metabolism of leukotrienes via omega-oxidation represents a major degradative and inactivating pathway of these biologically active icosanoids. Isonicotinic acid hydrazide (isoniazid) inhibited this process in rats in vivo, in the isolated perfused rat liver, and in hepatic microsomes. The in vivo catabolism of leukotriene E4 via N-acetyl-leukotriene E4 to its omega-oxidized metabolites was inhibited by 50% or 71% using single intravenous isoniazid doses of 0.6 mmol or 1.0 mmol/kg body mass, respectively. Isoniazid interfered with leukotriene catabolism at the initial omega-oxidation step, resulting in an accumulation of N-acetyl-leukotriene E4. Analogous although weaker inhibition of leukotriene omega-oxidation in vivo was observed by pretreatment with isonicotinic acid 2-isopropylhydrazide and monoacetyl hydrazine. In the isolated perfused liver, isoniazid at concentrations varying over 0.2-10 mM decreased the omega-oxidation of cysteinyl leukotrienes dose-dependently by up to 94%. omega-Oxidation of both leukotriene E4 and leukotriene B4 by rat liver microsomes was inhibited by isoniazid, isonicotinic acid 2-isopropylhydrazide, and monoacetyl hydrazine with half-maximal concentrations in the range of 5-15 mM. Our measurements indicate that the impairment of leukotriene omega-oxidation by isoniazid involves both cytochrome-P450-dependent enzyme systems responsible for omega-oxidation of leukotriene E4 and leukotriene B4. In effect, under isoniazid treatment one can expect a prolongation of the proinflammatory actions of endogenously produced leukotrienes.

Animals↗
PubMed2006

Public health impact of isoniazid-resistant Mycobacterium tuberculosis strains with a mutation at amino-acid position 315 of katG: a decade of experience in The Netherlands.

A previous limited study demonstrated that Mycobacterium tuberculosis isolates with a mutation at amino-acid position 315 of katG (Delta315) exhibited high-level resistance to isoniazid and were more frequently resistant to streptomycin. In the present study, isoniazid-resistant M. tuberculosis isolates from 8,332 patients in The Netherlands (1993-2002) were screened for the Delta315 mutation. Isoniazid resistance was found in 592 (7%) isolates, of which 323 (55%) carried Delta315. IS6110 restriction fragment length polymorphism analysis showed that Delta315 isolates occurred in clusters, suggesting recent transmission, at the same frequency as isoniazid-susceptible isolates. In contrast, other isoniazid-resistant isolates clustered significantly less frequently. Delta315 isolates were high-level isoniazid-resistant, streptomycin-resistant and multidrug-resistant significantly more often, and may have a greater impact on public health, than other isoniazid-resistant isolates.

Adolescent↗
PubMed1996

Activity of KRM-1648 in combination with isoniazid against Mycobacterium tuberculosis in a murine model.

The activity of KRM-1648, alone and in combination with isoniazid, was compared with those of isoniazid, rifampin, and the combination of rifampin plus isoniazid in a murine model of tuberculosis. Four-week-old female CD-1 mice were infected intravenously with approximately 10(7) viable Mycobacterium tuberculosis ATCC 35801 organisms. Treatment was started 1 week postinfection and was given by gavage 5 days per week. The duration of the treatment phase was 12 weeks, with groups of mice sacrificed at 2, 4, 6, 8, and 12 weeks. For the observation phase, additional groups of treated mice were sacrificed at 4, 8, 16, and 24 weeks after the cessation of treatment. Viable cell counts were determined from homogenates of the spleens and the right lungs. KRM-1648 was the most active single agent evaluated and resulted in no detectable CFUs in the spleens and lungs by the end of 6 weeks of treatment. Neither rifampin nor isoniazid reduced cell counts to undetectable levels, even after 12 weeks of treatment. The combination of KRM-1648 plus isoniazid was much more active than rifampin plus isoniazid. KRM-1648 plus isoniazid resulted in the apparent sterilization of organs at 6 months following the cessation of treatment. The promising activity of KRM-1648 may allow for ultrashort-course therapy of tuberculosis, i.e., treatment regimens of 4 months or less.

Animals↗
PubMed2002

Effects of gender, AIDS, and acetylator status on intrapulmonary concentrations of isoniazid.

The objective of the present study was to evaluate the effects of gender, AIDS, and acetylator status on the steady-state concentrations of orally administered isoniazid in plasma and lungs. Isoniazid was administered at 300 mg once daily for 5 days to 80 adult volunteers. Subjects were assigned to eight blocks according to gender, presence or absence of AIDS, and acetylator status. Blood was obtained prior to administration of the first dose, 1 h after administration of the last dose, and at the completion of bronchoscopy and bronchoalveolar lavage (BAL), which was performed 4 h after administration of the last dose. The metabolism of caffeine was used to determine acetylator status. Standardized bronchoscopy was performed without systemic sedation. The volume of epithelial lining fluid (ELF) recovered was calculated by the urea dilution method. Isoniazid concentrations in plasma, BAL fluid, and alveolar cells (ACs) were measured by high-performance liquid chromatography. AIDS status or gender had no significant effect on the concentrations of isoniazid in plasma at 1 or 4 h. Concentrations in plasma at 4 h and concentrations in ELF were greater in slow acetylators than fast acetylators. The concentration in plasma (1.85 +/- 1.60 microg/ml [mean +/- standard deviation; n = 80]) at 1 h following administration of the last dose was not significantly different from that in ELF (2.25 +/- 3.50 microg/ml) or ACs (2.61 +/- 5.01 microg/ml). For the entire study group, concentrations in plasma at 1 h were less than 1.0, 2.0, and 3.0 microg/ml for 34.7, 60, and 82.7% of the subjects, respectively; concentrations in ELF were less than 1.0, 2.0, and 3.0 microg/ml in 30 (37.5%), 53 (66.0%), and 58 (72.5%) of the subjects, respectively; and concentrations in ACs were less than 1.0, 2.0, and 3.0 microg/ml in 43 (53.8%), 59 (73.8%), and 65 (81.3%) of the subjects, respectively. The concentrations of orally administered isoniazid in plasma were not affected by gender or the presence of AIDS. The concentrations in plasma at 4 h and the concentrations in ELF, but not the concentrations in ACs, were significantly greater in slow acetylators than fast acetylators. Concentrations in plasma and lungs were low compared to recommended therapeutic concentrations in plasma and published MICs of isoniazid for Mycobacterium tuberculosis. The optimal concentrations of isoniazid in ACs and ELF are unknown, but these data suggest that the drug enters these compartments by passive diffusion and achieves concentrations similar to those found in plasma.

Acetylation↗
PubMed2005

Bactericidal action of gatifloxacin, rifampin, and isoniazid on logarithmic- and stationary-phase cultures of Mycobacterium tuberculosis.

The bactericidal activity of gatifloxacin, alone and in combination with isoniazid and rifampin, was studied on both exponential- and stationary-phase cultures of Mycobacterium tuberculosis strain H37Rv. On log-phase cultures, the bactericidal activity of gatifloxacin at 4 microg/ml was rapid and was very similar to that of isoniazid. At concentrations of 0.25 and 4 microg/ml, gatifloxacin enhanced the activity of isoniazid. Killing of the stationary-phase culture was biphasic. During the first 2 days, gatifloxacin at 4 microg/ml slightly increased the limited bactericidal activities of isoniazid and rifampin. However, no further additional bactericidal activity was found during further incubation with isoniazid alone or when gatifloxacin was added to either isoniazid or rifampin. This suggested that the stationary-phase culture contained a mixture of occasionally dividing bacilli that were killed during the first 2 days and true static persisters in the residual population that mimicked those in human lesions. In view of the failure of gatifloxacin to add to the sterilizing activity of isoniazid or rifampin during days 2 to 6 of exposure in the stationary-phase culture, it is unlikely to be a sterilizing drug that can be used to shorten the duration of treatment appreciably when it is added to present treatment regimens.

Anti-Bacterial Agents↗
PubMed2005

Molecular analysis of isoniazid-resistant Mycobacterium tuberculosis isolates from England and Wales reveals the phylogenetic significance of the ahpC -46A polymorphism.

The present study investigated the prevalence and diagnostic potential of the most commonly reported mutations associated with isoniazid resistance, katG 315Thr, katG 315Asn, inhA -15T, inhA -8A, and the oxyR-ahpC intergenic region, in a population sample of 202 isoniazid-resistant Mycobacterium tuberculosis isolates and 176 randomly selected fully sensitive isolates from England and Wales identified by using a directed oligonucleotide array and limited DNA sequencing. The strains were recovered from patients originating from 29 countries; 41 isolates were multidrug resistant. Mutations affecting katG 315, the inhA promoter, and the oxyR-ahpC intergenic region were found in 62.7, 21.9, and 30% of 169 genotypically distinct isoniazid-resistant isolates, respectively, whereas they were found in 0, 0, and 8% of susceptible strains, respectively. The frequency of mutation at each locus was unrelated to the resistance profile or previous antituberculous drug therapy. The commonest mutation in the oxyR-ahpC intergenic region, ahpC -46A, was present in 23.7% of isoniazid-resistant isolates and 7.5% of susceptible isolates. This proved to be a phylogenetic marker for a subgroup of M. tuberculosis strains originating on the Indian subcontinent, which shared IS6110-based restriction fragment length polymorphism and spoligotype features with the Delhi strain and Central Asian strain CAS1; and this marker is strongly associated with isoniazid resistance and the katG 315Thr mutation. In total, 82.8% of unrelated isoniazid-resistant isolates could be identified by analysis of just two loci: katG 315 and the inhA promoter. Analysis of the oxyR-ahpC intergenic region, although phylogenetically interesting, does not contribute significantly to further identification of isoniazid-resistant isolates.

Antitubercular Agents↗
PubMed1971

In vitro chemotherapeutic combinations against isoniazid-resistant Mycobacterium tuberculosis and Mycobacterium fortuitum.

It is an acceptable medical practice to use second-line antimycobacterial drugs in combination with isoniazid in treatment of isoniazid-resistant tuberculosis. Recent investigations have demonstrated the importance of determining chemotherapeutic interaction in instances of multiple antibiotic use. We studied the inhibitory effect of combinations of isoniazid with ethambutol, rifampin, ethionamide, cycloserine, viomycin, and kanamycin against three isoniazid-resistant strains of Mycobacterium tuberculosis and three strains of M. fortuitum. The isobologram technique with drug concentrations of 0.4 to 100 mug/ml was used. With the exception of single instances in which kanamycin plus isoniazid (M. tuberculosis strain 9999) and ethionamide plus isoniazid (M. fortuitum strain 2080) seemed to have a synergistic effect, neither synergy nor antagonism was noted for any of the combinations. These studies show that the combined use of isoniazid and a second line antimycobacterial agent results in vitro in indifferent inhibitory activity.

Antitubercular Agents↗
PubMed1995

Molecular mechanisms of isoniazid resistance in Mycobacterium tuberculosis and Mycobacterium bovis.

Genetic and biochemical studies have suggested a link between reduced catalase activity and resistance to isoniazid in Mycobacterium tuberculosis. In this study, we examined the molecular mechanisms of resistance to isoniazid with six in vitro mutants of the M. tuberculosis complex (Mycobacterium bovis and M. tuberculosis). Five of six mutants resistant to isoniazid were negative by catalase assays. Immunoblot analyses using a polyclonal antibody against the katG gene product (catalase-peroxidase) demonstrated that the enzyme is not produced in four of these isoniazid-resistant strains. A complete deletion of the katG gene was detected in only one of these isoniazid-resistant M. tuberculosis complex strains by Southern blot analyses. In two other resistant strains, partial deletions of the katG gene were identified. A point mutation which resulted in the insertion of a termination codon in the katG coding sequence caused a catalase-negative phenotype in a fourth strain. Of the two resistant strains which produce the enzyme, one was shown to be negative by a catalase assay. Single-stranded conformational polymorphism and DNA sequence analyses identified a mutation in the katG gene of this strain which may contribute to reduced enzymatic activity and subsequent isoniazid resistance. These data demonstrate that genetic alterations to the katG gene other than complete deletions are prevalent and may contribute significantly to the number of cases of isoniazid-resistant tuberculosis.

Base Sequence↗
PubMed2006

Effect of isoniazid prophylaxis on mortality and incidence of tuberculosis in children with HIV: randomised controlled trial.

OBJECTIVES: To investigate the impact of isoniazid prophylaxis on mortality and incidence of tuberculosis in children with HIV. DESIGN: Two centre prospective double blind placebo controlled trial. PARTICIPANTS: Children aged > or =8 weeks with HIV. INTERVENTIONS: Isoniazid or placebo given with co-trimoxazole either daily or three times a week. SETTING: Two tertiary healthcare centres in South Africa. MAIN OUTCOME MEASURES: Mortality, incidence of tuberculosis, and adverse events. RESULTS: Data on 263 children (median age 24.7 months) were available when the data safety monitoring board recommended discontinuing the placebo arm; 132 (50%) were taking isoniazid. Median follow-up was 5.7 (interquartile range 2.0-9.7) months. Mortality was lower in the isoniazid group than in the placebo group (11 (8%) v 21 (16%), hazard ratio 0.46, 95% confidence interval 0.22 to 0.95, P=0.015) by intention to treat analysis. The benefit applied across Centers for Disease Control clinical categories and in all ages. The reduction in mortality was similar in children on three times a week or daily isoniazid. The incidence of tuberculosis was lower in the isoniazid group (5 cases, 3.8%) than in the placebo group (13 cases, 9.9%) (hazard ratio 0.28, 0.10 to 0.78, P=0.005). All cases of tuberculosis confirmed by culture were in children in the placebo group. CONCLUSIONS: Prophylaxis with isoniazid has an early survival benefit and reduces incidence of tuberculosis in children with HIV. Prophylaxis may offer an effective public health intervention to reduce mortality in such children in settings with a high prevalence of tuberculosis. TRIAL REGISTRATION: Clinical Trials NCT00330304.

Africa South of the Sahara↗